The use of corticoids for a variety of indications is well known. They are used to treat, for example, asthma, rheumatoid arthritis and auto-immune diseases, including lupus, Scleroderma, Wegener's granulomatiosis, and the like. Some corticoids also exhibit progestational activity. One example is triamcinolone acetonide. The usefulness of such progestational corticoids is often impaired in some women by the side effects of such agents. For instance, those major side effect include menstrual irregularity and/or hot flashes. Such side effects can result in reluctance or even avoidance of the use of the corticoid as well as to restrict the medicinal formulations, such as inhalation therapies versus oral tablets or other systemic delivery systems or routes. Among females and males, reproductive capabilities can be impaired when corticoidal therapies are administered.
It has now been discovered that the side effects of the progestational corticoids can be modulated by the cojoint use of a selective estrogen receptor modulator (also known as an SERM, selective estrogen or anti-estrogen).
The use of an anti-estrogen in medical practice is known. While the anti-estrogen therapy which has been developed has been successful, it is not without problems. One reason is that endogenous hormone production implicates a hyper-activity of the hypothalamic-pituitary-gonadal axis. When estrogen binds to its receptors, there is a feedback mechanism which becomes activated and regulates the endogenous production of pituitary gonadotropins and, in turn, estrogen, so that the hormonal milieu remains within the physiological range. However, when an anti-estrogen binds to the estrogen receptors, altered estrogen feedback mechanisms are implicated in a pharmacological manner compared to what occurs when estrogen binds normally. The anti-estrogens themselves can induce multiple follicular growth which, in turn, causes the production of endogenous ovarian estrogens. One example is the use of clomiphene or tamoxifen for ovulation induction. At the time of the first anti-estrogen dose administration and continuing for some period of time, the endogenous estrogen produced as a consequence of the multiple follicular growth may not appear to pose a problem. However, at some point, which is totally unpredictable and which varies from individual to individual, endogenous estrogen can be produced such that the quantity of estrogen present can elevate blood levels well above 300 pg/ml. Indeed, estradiol concentration in plasma may exceed a few thousand pg/ml in some instances. Therefore, while the use of an anti-estrogen seeks to reduce or modify or eliminate the side effects of estrogen, its use over time may have the reverse effect by inducing an excess concentration of estrogen. Not only may the use of the anti-estrogen exaggerate the estrogen side effects which the therapeutic course seeks to avoid, but the anti-estrogen may also even eliminate the primary benefit of its administration in the first instance. For example, a "run away" endogenous estrogen can induce ovulation in those situations where the administration of the anti-estrogen was designed to provide contraception. This feature of anti-estrogen therapy makes the establishment and maintenance of appropriate dosages of anti-estrogen difficult and in some cases impossible, especially when the therapeutic goal is simultaneously to limit excessive estrogenic impact in one tissue while providing adequate estrogenic stimulation in another tissue.
In light of the characteristics of the anti-estrogen, the discovery that it can be used to modify the side effects of corticoid therapy is surprising and unexpected. By this combination, patients can better tolerate higher corticoid doses, with fewer side effects, as well as a broader array of drug delivery systems.
It is the object of this invention to modify the side effects of the use of progestational corticoids. This and other objects of the invention will become apparent to those of ordinary skill in the art from the following detailed description.